Cardiac fatty acid oxidation (FAO) is a major energy source for the adult mammalian heart. Intracellular triacylglyceride (TG) hydrolysis, which releases fatty acids (FAs) for the generation of ATP necessary for contractile function, plays a critical role in mediating cardiac substrate metabolism and function. Increased myocardial FAO and TG content have been associated with metabolic cardiomyopathy in obesity and diabetes. But mechanisms underlying hypertrophic cardiomyopathy in lipodystrophy remain elusive. Meanwhile, very little is known about the specific players that control myocardial TG metabolism and contractile function. Mutations at BSCL2 gene cause human type 2 Berardinelli-Seip Congenital Lipodystrophy (BSCL2) disease. Previously, we have generated global Bscl2 knockout (gKO) mice which recapitulate human BSCL2 with lipodystrophy and metabolic disorders. Here, our exciting preliminary data revealed cardiac hypertrophy with subsequently impaired contractile function in Bscl2 gKO mice. Especially, myocardial TG content was markedly reduced whereas cardiac FAO and glycogen content were substantially elevated in mice with global or cardiac-specific deletion (cKO) of Bscl2. Moreover, loss of myocardial Bscl2 increases the protein expression of cardiac adipose triglyceride lipase (ATGL), a critical enzyme that catalyzes the initial and rate-limiting step of intracellular TG hydrolysis. This leads us to hypothesize that Bscl2 regulates ATGL mediated triglyceride turnover and substrate metabolism in cardiomyocytes and is essential for cardiac efficiency and function. Aim 1 will test the hypothesis that myocardial Bscl2 deletion regulates cardiac triglyceride turnover and substrate metabolism by increasing ATGL expression. We will identify defects in myocardial substrate metabolism in mice with global and heart specific loss of Bscl2 and dissect the mechanistic links between myocardial Bscl2 loss and ATGL expression. Aim 2 will test the hypothesis that Bscl2 is essential for cardiac efficiency and function under physiological and pathological conditions. We will examine whether excessive cardiac FAO, independent of reduced cardiac TG content, impairs cardiac efficiency, mitochondrial function and energetics, leading to metabolic cardiomyopathy in unstressed states and lipodystrophy. The importance of Bscl2 regulated substrate metabolism in cardiac growth and function will be further examined in hemodynamic stress induced hypertrophic model. Together, these aims will provide novel mechanistic insights into the hypertrophic cardiomyopathy in complete lipodystrophy and uncover an essential role of an ER membrane protein (Bscl2) in regulating myocardial energy metabolism and function under normal and diseased conditions. These findings could provide new therapeutic approaches in metabolically treating cardiac disorders.